Dry eye disease (DED) is a common ocular disorder involving the aberrant production and stability of tear film, which results in damage to the ocular surface and is correlated with symptoms of ocular discomfort. DED is also recognized as keratoconjunctivitis sicca (KCS), sicca syndrome, keratitis sicca, xerophthalmia, dry eye syndrome (DES), dysfunctional tear syndrome (DTS), ocular surface disease (OSD) or dry eye. DED is caused by chronic instability of preocular tear film. Tear film instability can be triggered by insufficient tear production, or by poor tear film quality that results in increased tear evaporation. Furthermore, dry eye is typically categorized into two groups: (i) aqueous tear deficient dry eye disease; and (ii) evaporative dry eye disease.
DED is a result of changes to the lacrimal functional unit (LFU). The LFU is composed of the lacrimal glands, cornea, eyelids, meibomian glands, conjunctiva, goblet cells, and ocular nerves. The LFU is responsible for the sustained production of adequate tear film to consistently lubricate the ocular surface. Structural changes to the LFU can induce tear film instability and insufficiency, which in turn can lead to tear hyperosmolarity. Chronic osmotic stress from tear film can activate stress associated pathways in ocular surface epithelial cells, thereby triggering a pro-inflammatory response that involves a mix of chemokines, cytokines, and matrix metalloproteinases. The subsequent maturation of antigen-presenting cells (APC's) on the ocular surface leads to the migration, activation, and expansion of autoreactive T cell lymphocytes as well as other leukocytic classes in the LFU. The constant recruitment of pro-inflammatory leukocytes onto the ocular surface inflicts epithelium damage in the form of small abrasions and epithelium barrier defects. These abrasions can eventually progress to superficial punctuate keratitis, squamous metaplasia, extracellular matrix deposits, decreased goblet cell differentiation, increased epithelial cell turnover (epitheliopathy), and significant ocular surface nerve damage and neuropathy.
As DED progresses, lacrimal gland obstruction, meibomian gland orifice obstruction, thickened eyelid margins, cloudy, solid, or granular meibum secretion, eyelid telangiectasia, and meibomian gland dysfunction become common clinical features. In advanced cases, dry eye can cause fibrotic thickening of the cornea and conjunctiva, filamentous keratitis, mucoid clumping, trichiasis, symblepharon, keratinization of the eyelids and meibomian glands, corneal and conjunctival erosion and thinning, corneal and conjunctival neovascularization, corneal and conjunctival scarring, corneal ulceration, and corneal perforation. Most importantly, prolonged ocular surface inflammation can lead to moderate or absolute loss/atrophy of the meibomian glands, lacrimal glands, and conjunctival goblet cells, and subsequently a dramatic reduction in tear film production and the onset of permanent DED.
DED prevalence increases with age. The most common causes of dry eye are contact lens usage, autoimmune disorders, systemic drug effects, and refractive surgeries, particularly in middle-aged and older adults. DED also occurs in a higher percentage of women than men, especially in women entering menopause or pregnancy; hormone imbalances during menopause or pregnancy can cause lacrimal gland and ocular surface inflammation and tear film abnormalities.
Typically, clinicians prescribe artificial tear eyedrops and topical corticosteroids for short-term relief of DED. Antibiotics (e.g., tetracyclines and macrolides), non-steroidal anti-inflammatory agents, autologous serum drops, omega fatty acids, mucin secretagogues, artificial tears, and anti-inflammatory agents are also used to combat DED symptoms. In addition, prosthetic scleral lenses (i.e., PROSE) that also serve as supplemental tear reservoirs are increasingly being prescribed to enhance ocular surface hydration in patients with chronic DED. Hot eyelid compresses are often utilized to treat meibomian gland dysfunction, a primary driver of evaporative dry eye disease. In advanced cases of DED, punctual plugs can be installed to block tear drainage. In severe cases of dry eye, tarsorrhaphy surgery, tear duct cauterization, or amniotic membrane transplant might be required to reduce tear evaporation.
Currently there are only two pharmaceutical agents that are FDA approved for the treatment of dry eye: cylcosporine A ophthalmic emulsion (Restasis®) and lifitegrast ophthalmic solution (Xiidra™). Restasis® 0.05% is a topical immunomodulator indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca (Restasis® Prescribing Information). Xiidra™ 5% is a lymphocyte function-associated antigen (LFA-1) antagonist indicated for the treatment of signs and symptoms of dry eye disease (Xiidra™ Prescribing Information). Given the complexity, severity, and frequency of DED, and given the limited modes of action by which these two compounds treat dry eyes, there is a medical need for other dry eye therapies, particularly those with multiple modes of action that target the wider dry eye population and are effective and safe for early relief and long-term daily use as well.
In addition, both Xiidra® and Restasis® have anti-inflammatory properties and reduce cytokine release and T-cell activation. They work by reducing eye inflammation in people who suffer from dry eye syndrome. Unfortunately, there are no consistent and effective formulations that allow the efficient uptake of these active pharmaceutical ingredients for extended period into ocular surface tissues. Thus, these formulations require continual application for effective treatment of dry eye syndrome. While ointment or cream formulations may allow longer residence time, such formulations can cause discomfort and blurry vision.
Accordingly, there is a need for compositions and methods for effective treatment of dry eye syndrome that reduce or prevent the undesired local side effects observed in current formulations.